1. Field of the Invention
The present invention relates to a new epoxysuccinic acid derivative that inhibits thiol proteases such as cathepsin L and B and serves well as a prophylactic/therapeutic agent for bone diseases such as osteoporosis.
2. Description of Related Art
In bone tissue, bone resorption and formation occur constantly with a good balance to ensure bone homeostasis; bone diseases such as osteoporosis are caused when the balance shifts to the bone resorption side.
In recent years, various epoxy compounds possessing prophylactic/therapeutic activity against bone diseases have been reported (e.g., Japanese Patent Unexamined Publication No. 76-1987, European Patent Publication No. 269311).
Abbreviations for amino acids, peptides and others used in the present specification are based on abbreviations specified by the IUPAC-IUB Commission on Biochemical Nomenclature or abbreviations in common use in relevant fields. When an optical isomer may be present in amino acid, it is of the L-configuration, unless otherwise stated.
Currently, bone resorption suppressors such as estrogens and calcitonin are used to prevent and treat osteoporosis. However, these drugs do not inhibit the thiol protease secreted by the lysosome of osteoclasts. Also, administration of these therapeutic drugs does not always offer satisfactory effect because they are subject to limitation as to subject, and because their efficacy is uncertain in some cases.
With the above situation in mind, the present inventors took note of thiol proteases, especially cathepsin L [H. Kakegawa et al., FEBS Letters, Vol. 321, p. 247 (1993)], which has recently been shown to play a major role in bone resorption, and investigated microbial metabolites with the belief that a drug that selectively inhibits such cathepsin L will serve as a prophylactic/therapeutic agent for bone diseases such as osteoporosis.
Through intensive search, the present inventors found TAN-1756A, B, C and D, represented by the following structural formulas, in microorganisms belonging to the genus Chaetomium, and TAN-1854A and B, represented by the following structural formulas, in microorganisms belonging to the genus Tolypocladium, TAN-1803, represented by the following structural formula, in a microorganism belonging to the genus Trichoderma, and TAN-1868, represented by the following structural formula, in a microorganism belonging to the genus Aspergillus. The inventors also developed methods of synthesizing these compounds. The inventors made further investigations of epoxysuccinic acid derivatives based on these findings, and developed the present invention
______________________________________ ##STR2## Compound R.sup.2 R.sup.3 R.sup.4 ______________________________________ TAN-1756A ##STR3## H (CH.sub.2).sub.4 NH.sub.2 TAN-1756B ##STR4## H (CH.sub.2).sub.4 NH.sub.2 TAN-1854A ##STR5## (CH.sub.2).sub.3 NH.sub.2 (CH.sub.2).sub.4 NH.sub.2 TAN-1854B ##STR6## (CH.sub.2).sub.3 NH.sub.2 (CH.sub.2).sub.4 NH.sub.2 TAN-1756C ##STR7## H (CH.sub.2).sub.4 NH(CH.sub.2).sub.3 NH.sub.2 TAN-1756D ##STR8## H (CH.sub.2).sub.3 NH(CH.sub.2).sub.4 NH.sub.2 ______________________________________ ##STR9## Compound R.sup.23 R.sup.24 ______________________________________ TAN-1803 (CH.sub.2).sub.4 NH.sub.2 (CH.sub.2).sub.3 NH.sub.2 TAN-1868 (CH.sub.2).sub.5 NHCOCH.sub.3 H ______________________________________ [(S) indicates that the carbon atom marked therewith is in the Sconfiguration.]-